title: Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs.
abstract: Adipocyte glucose uptake in response to insulin is essential for physiological glucose homeostasis: stimulation of adipocytes with insulin results in insertion of the glucose transporter GLUT4 into the plasma membrane and subsequent glucose uptake. Here we establish that RAB10 and RAB14 are key regulators of GLUT4 trafficking that function at independent, sequential steps of GLUT4 translocation. RAB14 functions upstream of RAB10 in the sorting of GLUT4 to the specialized transport vesicles that ferry GLUT4 to the plasma membrane. RAB10 and its GTPase-activating protein (GAP) AS160 comprise the principal signaling module downstream of insulin receptor activation that regulates the accumulation of GLUT4 transport vesicles at the plasma membrane. Although both RAB10 and RAB14 are regulated by the GAP activity of AS160 in vitro, only RAB10 is under the control of AS160 in vivo. Insulin regulation of the pool of RAB10 required for GLUT4 translocation occurs through regulation of AS160, since activation of RAB10 by DENND4C, its GTP exchange factor, does not require insulin stimulation.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
authors.forename: L Amanda
authors.initials: LA
authors.lastname: Sadacca
authors.forename: Joanne
authors.initials: J
authors.lastname: Bruno
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wen
authors.forename: Wenyong
authors.initials: W
authors.lastname: Xiong
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D018274:Electroporation; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D051938:Munc18 Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C559260:Dennd4C protein, mouse; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D051938:Munc18 Proteins; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; C520736:Rab10 protein, mouse; C555882:Rab14 protein, mouse; C118120:Rala protein, mouse; D020691:rab GTP-Binding Proteins; D020725:ral GTP-Binding Proteins